Description: The clinical component of the University of Pittsburgh Autoimmune Center of Excellence proposes three clinical trials targeting autoimmune disorders involving three different organ systems. In the first trial, a non-Fc receptor-binding anti-CD3 humanized monoclonal antibody will be studied in patients with moderate to severe corticosteroid-refractory ulcerative colitis (UC). The specific immunomodulatory agent is Visilizumab, developed and manufactured by Protein Design Laboratories, Inc. This is a humanized IgG2 monoclonal antibody with amino acid substitutions in the CH2 domain of the Fc region, designed to reduce binding to the FcR and minimize toxicities associated with conventional anti-CD3 monoclonal antibodies. This study is based on preliminary data derived from a Phase I dose escalation trial of anti-CD3 in patients with UC led by investigators at the University of Pittsburgh. In the Phase I trial, five of five patients treated at the lowest proposed dose (15 mcg/kg on two consecutive days) were in clinical remission by day 30. In the new study, the investigators propose to enroll a total of 100 subjects who will be randomly assigned to two treatment groups at a 1:1 ratio. Group 1 will receive a placebo infusion and Group 2 will receive anti-CD3 mAb as a single IV injection. The primary end-point will be the proportion of patients with a clinical remission at week 4. No mechanistic studies are proposed in the context of this clinical trial. The second clinical trial is a Phase I dose escalation study of Visilizumab in patients with rheumatoid arthritis (RA). The study design is derived from the ongoing Phase I dose escalation study in UC at the University of Pittsburgh that served as the basis for the first clinical trial in this component. Twenty patients with active RA will be enrolled in the study. Eligible patients will receive Visilizumab at one of four dose levels (15, 45, 90, and 120 mcg/kg) administered as a single IV injection on each of two consecutive days. Five patients will be treated at each dose level. The primary objective of the study is to evaluate the safety and tolerability of Visilizumab when administered to patients with severe RA. The secondary objective is to obtain preliminary evidence of biologic activity in RA and document clinical responses, as defined by the ACR20 Response Criteria for Improvement. Clinical Trial 3 proposes to develop and test a microsphere-based vaccine for Type I diabetes mellitus (T1DM). The rationale for this trial is indirectly derived from data developed by the investigators in the NOD mouse using a dendritic cell-based approach to induce immune hyporesponsiveness to autoantigens involved in the pathogenesis of DM. In those studies, dendritic cells (DC) were modified with antisense oligonucleotides or decoys to modulate expression of CD40, CD80, CD86, and/or NF kappa B transcription factor. Because of appropriate concerns about the logistical and regulatory issues associated with the development of a cell-based therapy, the investigators propose to develop a microsphere-based vaccine consisting of dendritic and Langerhans cell (LC) mobilizing factors and immunoregulatory oligonucleotides that will arrest the deterioration of residual beta cell mass in new onset T1DM. The investigators postulate that injection of microspheres releasing chemokines into the skin will recruit DC and LC to the injection site. Immunoregulatory oligonucleotides incorporated into the microsphere will be taken up by the antigen presenting cells, converting them to a tolerizing phenotype. No pre-clinical data supporting the activity of these microspheres in the NOD model are provided. The proposed clinical trial is a safety trial of a vaccine for T1DM that will involve sequential administration of water-based microspheres containing LC and DC attractive chemokines, followed by injection of a second microsphere containing either NF kappa B oligonucleotides decoys or antisense oligonucleotides to CD40, CD80, and CD86. In Specific Aim 1, the investigators will assess the safety of single and multiple administrations of microsphere encapsulated combinations of DC/LC attracting chemokines and immunoregulators in normal volunteers and recent onset T1DM. In Aim 2, the investigators propose to examine the clinical efficacy of single and multiple administrations of microspheres in recent onset T1DM. In Aim 3, the investigators will evaluate immune responses in microsphere-treated individuals and correlate the results with clinical remission or improvement.